Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.

Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin prec...

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Autores principales:	Carlene S Starck, Andrew J Sutherland-Smith
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ed445096ce704ad78357e39a095529c7
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spelling	oai:doaj.org-article:ed445096ce704ad78357e39a095529c72021-11-25T06:25:56ZCytotoxic aggregation and amyloid formation by the myostatin precursor protein.1932-620310.1371/journal.pone.0009170https://doaj.org/article/ed445096ce704ad78357e39a095529c72010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20161792/?tool=EBIhttps://doaj.org/toc/1932-6203Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by beta-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis.Carlene S StarckAndrew J Sutherland-SmithPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 2, p e9170 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Carlene S Starck Andrew J Sutherland-Smith Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
description	Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by beta-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis.
format	article
author	Carlene S Starck Andrew J Sutherland-Smith
author_facet	Carlene S Starck Andrew J Sutherland-Smith
author_sort	Carlene S Starck
title	Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
title_short	Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
title_full	Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
title_fullStr	Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
title_full_unstemmed	Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
title_sort	cytotoxic aggregation and amyloid formation by the myostatin precursor protein.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/ed445096ce704ad78357e39a095529c7
work_keys_str_mv	AT carlenesstarck cytotoxicaggregationandamyloidformationbythemyostatinprecursorprotein AT andrewjsutherlandsmith cytotoxicaggregationandamyloidformationbythemyostatinprecursorprotein
_version_	1718413776982638592

Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.

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